Story Sandra, Jiang Liuwei, Leutou Alain S, Arya Dev P
NUBAD, LLC, Greenville, SC, United States.
Laboratory of Medicinal Chemistry, Department of Chemistry, Clemson University, Clemson, SC, United States.
Front Microbiol. 2025 Aug 7;16:1605813. doi: 10.3389/fmicb.2025.1605813. eCollection 2025.
Globally, it is predicted that by 2050, 10 million people will die annually because of infections with drug-resistant bacteria. Since antibacterial agents with novel mechanisms of action have not been developed in the past 30 years, there has been a surge of interest in combination therapies using existing drugs. The combination of aminoglycosides and colistin is often used to treat pneumonia caused by multidrug-resistant bacteria. The goal of this study is to investigate the relationship between the antibacterial activity of a peptide-neomycin library and polymyxin B in extensively drug-resistant and pandrug-resistant bacteria. The peptide-neomycin library contained conjugates with one or two amino acids linked to neomycin, rendering them unsuitable substrates for aminoglycoside-modifying enzymes. Neomycin- susceptible and neomycin-resistant members of , and were screened for synergy with polymyxin B using two-way checkerboard and time-kill methods. Most strains are resistant to amikacin, gentamicin, tobramycin, and plazomicin, and approximately half are susceptible to neomycin. strains have a similar resistance profile but was more susceptible to plazomicin. strains are most susceptible to a wide variety of aminoglycosides. Bacteria challenged with a combination of neomycin, other aminoglycosides, and polymyxin B exhibited an additive to indifferent relationship, whereas synergy was found with several neomycin-peptide conjugates containing cysteine, arginine, or tryptophan, lowering the minimal inhibitory concentration for the peptide-neomycin conjugate by 8-64-fold and polymyxin B by 2-8-fold. Cysteine, arginine, or tryptophan conjugates were the most effective against and carrying a 16S rRNA methyltransferase gene and a pandrug-resistant strain. Resistance to the combination of R-, C-, or RC-NEO conjugates and PB did not develop over a 14-day period in neomycin-susceptible strains of , and . Based on this survey of the peptide-neomycin library, circumvention of aminoglycoside-modifying enzymes and alluding to bacterial resistance is an important step toward the design and development of peptide aminoglycoside-based motifs for antimicrobial drug development.
据全球预测，到2050年，每年将有1000万人死于耐药菌感染。由于在过去30年中尚未开发出具有新作用机制的抗菌剂，因此人们对使用现有药物的联合疗法兴趣大增。氨基糖苷类和黏菌素的组合常用于治疗由多重耐药菌引起的肺炎。本研究的目的是调查肽 - 新霉素文库与多黏菌素B在广泛耐药菌和泛耐药菌中的抗菌活性之间的关系。肽 - 新霉素文库包含与新霉素连接一个或两个氨基酸的缀合物，使其成为氨基糖苷修饰酶的不合适底物。使用双向棋盘法和时间 - 杀菌法筛选了大肠埃希菌、肺炎克雷伯菌和鲍曼不动杆菌对新霉素敏感和耐药的菌株与多黏菌素B的协同作用。大多数大肠埃希菌菌株对阿米卡星、庆大霉素、妥布霉素和普拉唑米星耐药，约一半对新霉素敏感。肺炎克雷伯菌菌株具有相似的耐药谱，但对普拉唑米星更敏感。鲍曼不动杆菌菌株对多种氨基糖苷类最敏感。用新霉素、其他氨基糖苷类和多黏菌素B联合处理的细菌表现出相加至无关的关系，而在几种含有半胱氨酸、精氨酸或色氨酸的新霉素 - 肽缀合物中发现了协同作用，使肽 - 新霉素缀合物的最低抑菌浓度降低了8至64倍，多黏菌素B降低了2至8倍。半胱氨酸、精氨酸或色氨酸缀合物对携带16S rRNA甲基转移酶基因的大肠埃希菌和肺炎克雷伯菌以及泛耐药鲍曼不动杆菌菌株最有效。在新霉素敏感的大肠埃希菌、肺炎克雷伯菌和鲍曼不动杆菌菌株中，对R - 、C - 或RC - NEO缀合物与PB的联合耐药在14天内未出现。基于对肽 - 新霉素文库的这项调查，规避氨基糖苷修饰酶和暗示细菌耐药性是设计和开发基于肽 - 氨基糖苷基序的抗菌药物的重要一步。
